Clin Mol Hepatol > Volume 30(1); 2024 > Article
Chang, Jeong, and Jang: Recent updates on pharmacologic therapy in non-alcoholic fatty liver disease
Since there are currently no US Food and Drug Administration (FDA)-approved drugs for the treatment of non-alcoholic steatohepatitis (NASH), various NASH treatments are under development for a wide range of targets. Several promising agents have recently failed in phase 3 trials, including selosertib [1], elafibranor, and cenicriviroc [2], and now five pharmacologic agents—obeticholic acid (OCA), resmetirom, aramchol, lanifibranor, and semaglutide—are being evaluated in large, histology-based phase 3 trials (Table 1).
OCA, a farnesoid X receptor agonist, has been demonstrated to reduce hepatic fibrosis without worsening NASH in the 18-month interim analysis of the REGENERATE phase 3 trial [3], and its anti-fibrotic effect and long-term favorable safety profile have recently been validated [4]. However, in May 2023, the FDA rejected the new drug application of OCA for precirrhotic NASH, concerning safety issues such as hepatotoxicity, cholelithiasis, and pruritus, while its efficacy is modest. Resmetirom is a liver-targeted, thyroid hormone receptor β(THR-β)-selective agonist. Based on the promising results in the phase 2 clinical trial [5], phase 3 trials evaluating the efficacy of resmetirom in patients with NASH presenting with compensated cirrhosis (MAESTRO-NASH-Outcomes trial) and stage 2–3 fibrosis (MAESTRO-NASH) are ongoing. In the interim analysis of MAESTRO-NASH trial, which included 955 patients, histological NASH resolution and fibrosis reduction end points were achieved after 52 weeks of treatment [6]. Until now resmetirom is the only drug showing both NASH and fibrosis improvement in a phase 3 trial. The antidiabetic drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP), are attractive candidates for the treatment of NASH, considering their beneficial metabolic effects. These are incretins that stimulate insulin secretion from pancreatic β cells in response to food ingestion. Semaglutide, a GLP-1 RA, showed a significant dose-dependent NASH resolution without worsening of fibrosis in a phase 2 randomized controlled trial (RCT) involving patients with NASH and stage 1–3 fibrosis [7]. A phase 3 trial of semaglutide for NASH-related fibrosis (ESSENCE trial) is currently underway. However, in a recent phase 2 RCT for NASH-related cirrhosis, semaglutide did not improve fibrosis or NASH resolution, although it showed improvements in cardiometabolic parameters [8]. Effective drug therapy for NASH-related cirrhosis is challenging, as belafectin [9], selonsertib [1], and OCA also failed in this field. Tirzepatide, a dual agonist for GIP and GLP-1 receptors recently approved for type 2 diabetes mellitus, has been shown to reduce hepatic fat content as well as weight loss, suggesting a potential benefit for NASH [10,11]. Additionally, cotadutide, a dual receptor agonist of GLP-1/glucagon [12], and efocipegtrutide, a novel GLP-1/GIP/glucagon triple-receptor co-agonist [13,14], have shown potential as a treatment for NASH. Since glucagon receptors, unlike GIP and GLP-1, are highly expressed in the liver, glucagon agonism has significant impact on metabolism in the liver and extrahepatic tissues [15]. Another antidiabetic drug, dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, has been shown to reduce liver steatosis and fibrosis in small RCTs and meta-analysis [16,17]. A phase 3 trial (DEAN trial) to assess the efficacy and safety of dapagliflozin in improving NASH and metabolic risk factors is still ongoing. A phase 3 trial of aramchol (AMOR trial) was initiated on the basis of the observed safety and changes in liver histology in the phase 2b trial [18]. After the open-label part of the AMOR trial has met its objective, the manufacturer changed its proposed clinical studies with aramchol meglumine instead of aramchol free acid. Accordingly, initiation of the double-blind part is being suspended upon the manufacturer’s strategy. In a phase 2b clinical trial of lanifibranor in patients with NASH and significant fibrosis, lanifibranor achieved both endpoints of NASH resolution and fibrosis improvement, together with an improvement in lipid profile and insulin resistance [19]. A phase 3 trial of lanifibranor in patients with NASH and stage 2–3 fibrosis (NATiV3 trial) is currently ongoing. FGF21 is a non-mitogenic hormone that regulates glucose and lipid metabolism and modulates adiponectin secretion. Recently, pegbelfermin has failed to demonstrate significant reductions in liver fibrosis in patients with NASH [20,21]. In contrast, pegozafermin, a long-acting glycopegylated recombinant FGF21 analogue, led to significant improvements in fibrosis and NASH resolution in patients with stage 2–3 fibrosis (ENLIVEN trial) [22]. These promising results provide the basis for the advancement of pegozafermin into phase 3 development. An update on current pharmacological therapies for non-alcoholic fatty liver disease is summarized in Figure.
Several agents, including THR-ß-selective agonist, antidiabetic drugs, and FGF21 agonists show promise as new therapeutics for NASH, and their efficacy in improving both inflammation and fibrosis, with a long-term safety profile, is expected. Considering the heterogeneity of the disease and the various treatment responses observed in clinical trials for individual drugs, it is challenging to define effective drugs for all patients with NASH [23]. Accordingly, combination treatment or personalized treatment approaches may provide a higher response in the context of disease mechanisms.

ACKNOWLEDGMENTS

This work was supported by the Soonchunhyang University Research Fund and the National Research Foundation of Korea (NRF) grant funded by the Korea government (2021R1I1A3059993, RS-2023-00251607).

FOOTNOTES

Authors’ contribution
Young Chang drafted and revised the manuscript. Soung Won Jeong designed the concept and revised the manuscript. Jae Young Jang conducted the literature search and reviewed the manuscript.
Conflicts of Interest
The authors have no conflicts to disclose.


cmh-2023-0356f1.jpg
Table 1.
Clinical trials evaluating the efficacy of various agents for nonalcoholic steatohepatitis
Drug Mechanism Phase Trial Fibrosis stage Size (n) Current status
Obeticholic acid FXR agonist 3 REGENERATE (NCT02548351) NASH fibrosis (F1-3) 2,480 Active, not recruiting
FDA rejected the new drug application of OCA for pre-cirrhotic NASH
Resmetirom Selective THR-β agonist 3 MAESTRO-NASH (NCT03900429) NASH fibrosis (F2-3) 2,000 Ongoing
Semaglutide GLP-1 RA 3 ESSENCE (NCT04822181) NASH fibrosis (F2-3) 1,200 Ongoing
Dapagliflozin SGLT2 inhibitor 3 DEAN (NCT03723252) NASH 100 Ongoing
Aramchol SCD1 inhibitor 3 ARMOR (NCT04104321) NASH fibrosis (F2-3) 2,000 Part I (open-label) met its objective
Part II (double-blind) was suspended
Lanifibranor Pan-PPAR agonist 3 NATiV3 (NCT04849728) NASH fibrosis (F2-3) 2,000 Ongoing
Pegozafermin FGF21 agonist 2 ENLIVEN (NCT04929483) NASH fibrosis (F2-3) 222 Completed
Fibrosis significantly improved ≥1 stage without worsening of NASH

FDA, US Food and Drug Administration; OCA, obeticholic acid; GIP, glucose-dependent insulinotropic polypeptide; GLP-1 RA, glucagone-like peptide-1 receptor agonists; FGF, fibroblast growth factor; FXR, farnesoid X receptor; NASH, nonalcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; SCD, stearoyl coenzyme A desaturase; SGLT, sodium-glucose cotransporter; THR, thyroid hormone receptor.

Abbreviations

CYP
cytochrome P
FAO
fatty acid oxidation
FGF
fibroblast growth factor
FGFR
fibrosis growth factor receptor
FXR
farnesoid X receptor
GLP-1 RA
glucagonelike peptide-1 receptor agonists
GIP
glucose-dependent insulinotropic polypeptide
PPAR
peroxisome proliferator-activated receptor
MPC
mitochondrial pyruvate carrier
SCD
stearoyl coenzyme A desaturase
SGLT2
sodium glucose co-transporter 2
TCA cycle
tricarboxylic acid cycle
TG
triglyceride
THR
thyroid hormone receptor
FDA
US Food and Drug Administration
NASH
non-alcoholic steatohepatitis
OCA
obeticholic acid
RCT
randomized controlled trial

REFERENCES

1. Harrison SA, Wong VW, Okanoue T, Bzowej N, Vuppalanchi R, Younes Z, et al. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials. J Hepatol 2020;73:26-39.
crossref pmid
2. Anstee QM, Neuschwander-Tetri BA, Wai-Sun Wong V, Abdelmalek MF, Rodriguez-Araujo G, Landgren H, et al. Cenicriviroc lacked efficacy to treat liver fibrosis in nonalcoholic steatohepatitis: AURORA Phase III Randomized Study. Clin Gastroenterol Hepatol 2023 Apr 13. doi: 10.1016/j.cgh.2023.04.003.
crossref pmid
3. Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. Obeticholic acid for the treatment of nonalcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2019;394:2184-2196.
pmid
4. Sanyal AJ, Ratziu V, Loomba R, Anstee QM, Kowdley KV, Rinella ME, et al. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of precirrhotic fibrosis due to non-alcoholic steatohepatitis. J Hepatol 2023 Jul 28. doi: 10.1016/j.jhep.2023.07.014.

5. Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2019;394:2012-2024.
crossref pmid
6. Harrison S, Bedossa P, Guy C, Schattenberg J, Loomba R, Taub R, et al. Primary results from MAESTRO-NASH a pivotal phase 3 52-week serial liver biopsy study in 966 patients with NASH and fibrosis. J Hepatol 2023;78:S1.
crossref
7. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med 2021;384:1113-1124.
crossref pmid
8. Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjær MS, Krarup N, et al. Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol 2023;8:511-522.
crossref pmid
9. Chalasani N, Abdelmalek MF, Garcia-Tsao G, Vuppalanchi R, Alkhouri N, Rinella M, et al. Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension. Gastroenterology 2020;158:1334-1345 e5.
crossref pmid
10. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022;387:205-216.
crossref pmid
11. Gastaldelli A, Cusi K, Fernández Landó L, Bray R, Brouwers B, Rodríguez Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol 2022;10:393-406.
crossref pmid
12. Robertson D, Challis B, Daniels SJ, Sarv J, Sanchez J, Schumi J, et al. PROXYMO demonstrates safety and efficacy of cotadutide, a novel incretin co-agonist in biopsy-proven non-cirrhotic NASH with fibrosis. Oral abstract. Hepatology 2021;74:1383A.
crossref pmid pdf
13. Choi J, Kim JK, Lee SM, Kwon H, Lee J, Bae S, et al. Therapeutic effect of a novel long-acting GLP-1/GIP/Glucagon Triple Agonist (HM15211) in CDHFD-induced NASH and fibrosis mice. Diabetes 2020;69(Suppl 1):1830-P.

14. Abdelmalek M, Choi J, Kim Y, Seo K, Hompesch M, Baek S. HM15211, a novel GLP-1/GIP/Glucagon triple-receptor coagonist significantly reduces liver fat and body weight in obese subjects with non-alcoholic fatty liver disease: A Phase 1b/2a, multi-center, randomized, placebo-controlled trial. J Hepatol 2020;73:S124.
crossref
15. Tilg H, Byrne CD, Targher G. NASH drug treatment development: challenges and lessons. Lancet Gastroenterol Hepatol 2023;8:943-954.
crossref pmid
16. Sun L, Deng C, Gu Y, He Y, Yang L, Shi J. Effects of dapagliflozin in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials. Clin Res Hepatol Gastroenterol 2022;46:101876.
crossref pmid
17. Shimizu M, Suzuki K, Kato K, Jojima T, Iijima T, Murohisa T, et al. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes Metab 2019;21:285-292.
crossref pmid pdf
18. Ratziu V, de Guevara L, Safadi R, Poordad F, Fuster F, Flores-Figueroa J, et al. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat Med 2021;27:1825-1835.
pmid
19. Francque SM, Bedossa P, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, et al. A randomized, controlled trial of the Pan-PPAR agonist lanifibranor in NASH. N Engl J Med 2021;385:1547-1558.
crossref pmid
20. Loomba R, Sanyal AJ, Nakajima A, Neuschwander-Tetri BA, Goodman ZD, Harrison SA, et al. Pegbelfermin in patients with nonalcoholic steatohepatitis and stage 3 fibrosis (FALCON 1): A randomized phase 2b study. Clin Gastroenterol Hepatol 2023;doi: 10.1016/j.cgh.2023.04.011.
crossref pmid
21. Abdelmalek MF, Sanyal AJ, Nakajima A, Neuschwander-Tetri BA, Goodman ZD, Harrison SA, et al. Pegbelfermin in patients with nonalcoholic steatohepatitis and compensated cirrhosis (FALCON 2): A randomized phase 2b study. Clin Gastroenterol Hepatol 2023;doi: 10.1016/j.cgh.2023.04.012.
crossref pmid
22. Loomba R, Sanyal AJ, Kowdley KV, Bhatt DL, Alkhouri N, Frias JP, et al. Randomized, controlled trial of the FGF21 analogue pegozafermin in NASH. N Engl J Med 2023;389:998-1008.
crossref pmid
23. An J, Sohn JH. Pharmacological advances in the treatment of nonalcoholic fatty liver diseases: focused on global results of randomized controlled trials. Clin Mol Hepatol 2023;29(Suppl):S268-S275.
crossref pmid pmc pdf

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